Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME

Experimental evidence indicates that the renal circulation is more sensitive to the effects of nitric oxide (NO) synthesis inhibition than other vascular beds. To explore whether in men the NO-mediated vasodilator tone is greater in the renal than in the systemic circulation, the effects of three different intravenous infusions of NG-nitro-L-arginine methyl ester (L-NAME; 1, 5, and 25 microg. kg-1. min-1 for 30 min) or placebo on mean arterial pressure (MAP), systemic vascular resistance (SVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), and fractional sodium and lithium excretion (FENa and FELi) were studied in 12 healthy subjects, each receiving randomly two of the four treatments on two different occasions. MAP was measured continuously by means of the Finapres device, and stroke volume was calculated by a model flow method. GFR and RBF were estimated from the clearances of radiolabeled thalamate and hippuran. Systemic and renal hemodynamics were followed for 2 h after start of infusions. During placebo, renal and systemic hemodynamics and FENa and FELi remained stable. With the low and intermediate L-NAME doses, maximal increments in SVR and RVR were similar: 20.4 +/- 19.6 and 23.5 +/- 16.0%, respectively, with the low dose and 31.4 +/- 26.7 and 31.2 +/- 14.4%, respectively, with the intermediate dose (means +/- SD). With the high L-NAME dose, the increment in RVR was greater than the increment in SVR. Despite a decrease in RBF, FENa and FELi did not change with the low L-NAME dose, but they decreased by 31.2 +/- 11.0 and 20.2 +/- 6.3%, respectively, with the intermediate dose and by 70.8 +/- 8.1 and 31.5 +/- 15.9% with the high L-NAME dose, respectively. It is concluded that in men the renal circulation is not more sensitive to the effects of NO synthesis inhibition than the systemic circulation and that the threshold for NO synthesis inhibition to produce antinatriuresis is higher than the threshold level to cause renal vasoconstriction

Two canine CD1a proteins are differentially expressed in skin

Lipid antigens are presented to T cells by the CD1 family of proteins. In this study, we characterize the complete dog (Canis familiaris) CD1 locus, which is located on chromosome 38. The canine locus contains eight CD1A genes (canCD1A), of which five are pseudogenes, one canCD1B, one canCD1C, one canCD1D, and one canCD1E gene. In vivo expression of canine CD1 proteins was shown for canCD1a6, canCD1a8, and canCD1b, using a panel of anti-CD1 monoclonal antibodies (mAbs). CanCD1a6 and canCD1a8 are recognized by two distinct mAbs. Furthermore, we show differential transcription of the three canCD1A genes in canine tissues. In canine skin, the transcription level of canCD1A8 was higher than that of canCD1A6, and no transcription of canCD1A2 was detected. Based on protein modeling and protein sequence alignment, we predict that both canine CD1a proteins can bind different glycolipids in their groove. Besides differences in ectodomain structure, we observed the unique presence of three types of cytoplasmic tails encoded by canCD1A genes. cDNA sequencing and expressed sequence tag sequences confirmed the existence of a short, human CD1a-like cytoplasmic tail of four amino acids, of an intermediate length form of 15 amino acids, and of a long form of 31 amino acids

The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis

In contrast to microbially triggered inflammation, mechanisms promoting sterile inflammation remain poorly understood. Damage-associated molecular patterns (DAMPs) are considered key inducers of sterile inflammation following cell death, but the relative contribution of specific DAMPs, including high–mobility group box 1 (HMGB1), is ill defined. Due to the postnatal lethality of Hmgb1-knockout mice, the role of HMGB1 in sterile inflammation and disease processes in vivo remains controversial. Here, using conditional ablation strategies, we have demonstrated that epithelial, but not bone marrow–derived, HMGB1 is required for sterile inflammation following injury. Epithelial HMGB1, through its receptor RAGE, triggered recruitment of neutrophils, but not macrophages, toward necrosis. In clinically relevant models of necrosis, HMGB1/RAGE-induced neutrophil recruitment mediated subsequent amplification of injury, depending on the presence of neutrophil elastase. Notably, hepatocyte-specific HMGB1 ablation resulted in 100% survival following lethal acetaminophen intoxication. In contrast to necrosis, HMGB1 ablation did not alter inflammation or mortality in response to TNF- or FAS-mediated apoptosis. In LPS-induced shock, in which HMGB1 was considered a key mediator, HMGB1 ablation did not ameliorate inflammation or lethality, despite efficient reduction of HMGB1 serum levels. Our study establishes HMGB1 as a bona fide and targetable DAMP that selectively triggers a neutrophil-mediated injury amplification loop in the setting of necrosis

The catabolic-to-anabolic shift seen in the canine osteoarthritic cartilage treated with knee joint distraction occurs after the distraction period

Background Cartilage regenerative mechanisms initiated by knee joint distraction (KJD) remain elusive. Animal experiments that are representative for the human osteoarthritic situation and investigate the effects of KJD at consecutive time points could be helpful in this respect but are lacking. This study investigated the effects of KJD on the osteoarthritic joint of dogs on two consecutive timepoints. Methods Osteoarthritis was bilaterally induced for 10 weeks in 12 dogs using the groove model. Subsequently, KJD was applied to the right hindlimb for 8 weeks. The cartilage, subchondral bone and synovial membrane were investigated directly after KJD treatment, and after 10 weeks of follow-up after KJD treatment. Macroscopic and microscopic joint tissue alterations were investigated using the OARSI grading system. Additionally, proteoglycan content and synthesis of the cartilage were assessed biochemically. RT-qPCR analysis was used to explore involved signaling pathways. Results Directly after KJD proteoglycan and collagen type II content were reduced accompanied by decreased proteoglycan synthesis. After 10 weeks of follow-up, proteoglycan and collagen type II content were partly restored and proteoglycan synthesis increased. RT-qPCR analysis of the cartilage suggests involvement of the TGF-β and Notch signalling pathways. Additionally, increased subchondral bone remodelling was found at 10 weeks of follow-up. Conclusion While the catabolic environment in the cartilage is still present directly after KJD, at 10 weeks of follow-up a switch towards a more anabolic joint environment was observed. Further investigation of this timepoint and the pathways involved might elucidate the regenerative mechanisms behind KJD. The Translational Potential of this Article Further elucidation of the regenerative mechanisms behind KJD could improve the existing KJD treatment. Furthermore, these findings could provide input for the discovery or improvement of other joint regenerative treatment strategies

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Recent Results on Lead-Ion Accumulation in LEAR for the LHC

To prepare dense bunches of lead ions for the LHC it has been proposed to accumulate the 4.2 MeV/u linac beam in a storage ring with electron cooling. A series of experiments is being performed in the low-energy ring LEAR to test this technique. First results were already reported at the Beam Crystallisation Workshop in Erice in November 1995. Two more recent runs to complement these investigations were concerned with: further study of the beam lifetime; the dependence of the cooling time on optical settings of the storage ring and on neutralization of the electron beam; tests in view of multiturn injection. New results obtained in these two runs in December 1995 and in April 1996 will be discussed in this contribution

Barriers and Best Practices for the Circular Economy

Introduction We’re living in an exciting era. Rather than just another societal transition, we’re going through a fundamental societal transformation. Ecologist Joanne Macy calls this period ‘The Great Turning’: a period wherein we change from an industrial growth society into a life sustaining system’. Macy: “The most remarkable feature of this historical moment on Earth is not that we are on the way to destroying the world; we've actually been on the way for quite a while. It is that we are beginning to wake up, as from a millennia-long sleep, to a whole new relationship to our world, to ourselves and each other.” It is with these eyes that we have to see the rise of the Circular Economy. The Circular Economy is not just another trend in business; it’s the start of a completely new economic reality. The Circular Economy is the starting point for regenerative economics; for a new business-as-usual that - first and foremost - serves life and is based upon a fundamentally new value-paradigm. The future of success in business is about doing good for all stakeholders and creating benefit; not just profit. The Circular Economy demands next level thinking-and-doing in business, and there is no one more willing and able than the next generation of young professionals. It is therefore with great pride and pleasure that I present to you this publication of the SMO Promovendi. It offers fresh perspectives of a group of promising young scientists. All aspiring changemakers. It’s made with love and with the best of intentions; to help the Circular Economy forward